Benzodiazepine derivatives and uses thereof

Abstract

The present disclosure provides compounds and compositions capable of extending lifespan, and methods of use thereof.

We claim: 
     
       1. A compound having the structure of Formula (II), (IIa), or (IIb) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         A 1  and A 2  each independently represent a heterocyclic ring; 
         R 1  and R 2  are each independently an alkyl group; 
         Z 1  is a linking group; 
         n 1  and n 2  are each independently an integer having a value of 1 to 5; 
         Z 2  is a linking group; 
         L 1 , when present, is a linking group attached to the SO 2  via a heteroatom selected from O, S, and N, and is selected such that cleavage of the bond between L 1  and SO 2  promotes cleavage of the bond between L 1  and Z 1 , A 1 , or A 2  to release the active agent; 
         X 1  is —O—, —CR b   2 —, or —NR a —; 
         Ar is selected from aryl or heteroaryl; 
         Y 1  is —(CR b   2 ) y N(R a )—, —(CR b   2 ) y O—, or —(CR b   2 ) y S—, positioned such that the N, O, or S atom is attached to TG if y is 1-10; wherein X 1  and Y 1  are positioned on adjacent atoms of Ar; 
         TG is a triggering group that, when activated, generates an N, O, or S atom capable of reacting with the SO 2  to displace Z 1 , A 1 , or A 2  and form a 5-6-membered ring including X 1 —SO 2  and the intervening atoms of Ar; 
         w and x are each independently an integer having a value of 0 or 1; 
         each R a  is independently hydrogen or lower alkyl; 
         each R b  is independently hydrogen or lower alkyl; or 
         two R b , together with the carbon atom to which they are attached, form a 3-5-membered ring; and 
         y is an integer having a value of 0-10. 
       
     
     
       2. The compound of  claim 1 , wherein X 1  is —O—. 
     
     
       3. The compound of  claim 1 , wherein Ar is phenyl or naphthyl. 
     
     
       4. The compound of  claim 1 , wherein Z 2  is a linking group comprising one or more groups selected from isocyanide, isothiocyanide, 2-pyridyl disulfide, haloacetamide (—NHC(O)CH 2 -halo), maleimide, diene, alkene, halide, tosylate (TsO-), aldehyde, sulfonate (R—SO 3   − ), 
       
         
           
           
               
               
           
         
         phosphonic acid (—P(═O)(OH) 2 ), ketone, C8-C10 cycloalkynyl, —OH, —NHOH, —NHNH 2 , —SH, carboxylic acid (—COOH), acetylene (—C≡CH), azide (—N 3 ), amino (—NH 2 ), sulfonic acid (—SO 3 H), an alkynone derivative (—C(O)C≡CR a  wherein R a  is C 1-10  alkyl), and dihydrogen phosphate (—OP(═O)(OH) 2 ). 
       
     
     
       5. The compound of  claim 1 , wherein x is 0. 
     
     
       6. The compound of  claim 5 , wherein TG is —NO 2 , —OC(O)(CH 2 ) r C(O)R 1 , NHNH 2 , —BR 2 R 3 , or 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 1 -C 6  alkyl; 
         R 2  and R 3  are each independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy; 
         R 4 , R 5 , R 6 , and R 7  are each independently hydrogen or C 1 -C 6  alkyl; and 
         r is an integer having a value of 1, 2, 3, 4, or 5. 
       
     
     
       7. The compound of  claim 1 , wherein TG is selected from: 
       
         
           
           
               
               
           
         
         wherein: 
         each R 21  is independently hydrogen or acetyl; and 
         R 22  is hydrogen or lower alkyl. 
       
     
     
       8. The compound of  claim 1 , wherein TG is selected from —NO 2 , —C(O)—(CH 2 ) 2 C(O)-alkyl, and nitrobenzyl. 
     
     
       9. A conjugate having the structure of Formula (III):
   (D-L) dl -LG-(CB) cb    (III)
 
 or a pharmaceutically acceptable salt thereof, 
 wherein: 
 LG is a linking group; 
 CB is a cell-binding agent; 
 cb and dl are each independently integers having a value of 1 to about 20; and 
 each D-L independently is a group having the structure of a compound of  claim 1 . 
 
     
     
       10. The conjugate of  claim 9 , wherein LG is a C 10 -C 100  linear or branched, saturated or unsaturated alkylene moiety comprising at least two of the following:
 (i) at least one heteroatom selected from —NH—, —C(═O), —O—, —S— and —P—; 
 (ii) at least one heteroarylene; 
 (iii) at least one amino acid moiety, sugar bond, peptide bond, or amide bond; and 
 (iv) one or more substitutents selected from the group consisting of C 1 -C 20  alkyl, C 6 -C 20  aryl C 1 -C 8  alkyl, —(CH 2 ) s COOH, and —(CH 2 ) p NH 2 , s is an integer having a value of 0 to 10, and p is an integer having a value of 1 to about 10. 
 
     
     
       11. The conjugate of  claim 9 , wherein LG is a functional group that can be produced through a click chemical reaction. 
     
     
       12. The conjugate of  claim 9 , wherein LG is: 
       
         
           
           
               
               
           
         
         wherein: 
         * represents the point to attachment to (D-L) dl ; 
         ** represent the point of attachment to CB; 
         each V is independently a single bond, —O—, —S—, —NR 21 —, —C(O)NR 22 —, —NR 23 C(O)—, —NR 24 SO 2 —, or —SO 2 NR 25 —; 
         R 21 , R 22 , R 23 , R 24 , and R 25  are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -C 20 )aryl, or (C 1 -C 6 )alkyl(C 3 -C 20 )heteroaryl; 
         r is an integer having a value of 1 to about 10; 
         p is an integer having a value of 0 to about 10; 
         q is an integer having a value of 1 to about 10; and 
         L 3  is a single bond. 
       
     
     
       13. The conjugate of  claim 9 , wherein LG comprises (CH 2 ) b , L c , (P 1 ) a , W a1 , W a2 , W a3 , Y 3  and Y 4  groups connected to each other in a linear chain by covalent bonds,
 wherein: 
 W a1 , W a2 , and W a3  are each independently —NH—, —C(O)—, or —CH 2 —; 
 P 1  is an amide bond, an amino acid residue, or a peptide; 
 L c  is alkylene; 
 Y 3  is —(CH 2 ) q —(CH 2 CH 2 X 4 ) o — or —(CH 2 ) q —(X 4 CH 2 CH 2 X 3 ) o —; 
 X 3  and X 4  are each independently —O—, —S—, —NH— or —CH 2 —; 
 Y 4  is a single bond or a group selected from: 
 
       
         
           
           
               
               
           
         
         W b2  is an amide bond or triazolylene; 
         a is 0 to 10; 
         b, c, and d are each independently an integer having a value of 1 to about 10; and 
         and q are each independently an integer having a value of 1 to about 10. 
       
     
     
       14. The conjugate of  claim 9 , wherein LG is a linking group of Formula (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), or (IIIj): 
       
         
           
           
               
               
           
         
         wherein: 
         * represents the point to attachment to (D-L) dl : 
         ** represent the point of attachment to CB: 
         R e  is alkyl: 
         L 4  is a spacer moiety, unsubstituted or substituted with one or more C 1 -C 6  alkyl, C 5 -C 14  aryl, and C 3 -C 8  heteroaryl, wherein the alkyl, aryl and heteroaryl are unsubstituted or substituted with one or more substituents selected from C 1 -C 10  alkyl, —(CH 2 ) u NH 2 , —(CH 2 ) u NR u1 R u2 , —(CH 2 ) u CO 2 H, —(CH 2 ) u CO 2 R u1 , and —(CH 2 ) u SO 2 R u3 , wherein R u1 , R u2 , and R u3  are each independently hydrogen, C 1 -C 15  alkyl, C 6 -C 20  aryl or C 3 -C 10  heteroaryl; and u is an integer having a value of 1 to 10: 
         W b1  and W b2  are each independently —C(O)NH—, —NHC(O)—, 
       
       
         
           
           
               
               
           
         
         R 12  is hydrogen, alkyl, an amino acid side chain, —(CH 2 ) s C(O)R 13  or —(CH 2 ) p NR 14 R 15 ; 
         R 13  is OH or —NH(CH 2 ) s′ (X 4 CH 2 CH 2 ) s″ Z″—(CB) m ; 
         R 14  and R 15  are each independently hydrogen or —C(O)(CH 2 ) s′ (X′″CH 2 CH 2 ) s″ Z″—(CB) m ; 
         Z″ is a linking group connecting CB to the remainder of R 14  or R 15 : or Z″ is a linking group comprising a reactive group: 
         X′″ is —O—, —S—, —NH—, or —CH 2 —; 
         s and s″ are each independently an integer having a value of 0 to about 10; 
         m is an integer having a value of 0 or 1; 
         X 4  and X 5  are each independently —O—, —S—, —NH—, or —CH 2 —; and 
         a, b, c, d, e, o, p, s′ and qq are each independently an integer having a value of 1 to about 10. 
       
     
     
       15. The conjugate of  claim 9 , wherein the cell-binding agent binds to target cells selected from tumor cells, virus infected cells, microorganism cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes; cells expressing the CD4, CD6, CD19, CD20, CD22, CD30, CD33, CD37, CD38, CD40, CD44, CD56, EpCAm, CanAg, CALLA, or Her-2 antigens; Her-3 antigens or cells expressing insulin growth factor receptor, epidermal growth factor receptor, and folate receptor. 
     
     
       16. The conjugate of  claim 15 , wherein the tumor cells are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, and testicular cancer cells. 
     
     
       17. The conjugate of  claim 15 , wherein the cell-binding agent is an antibody, a single chain antibody, an antibody fragment that specifically binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that specifically binds to the a target cell, a chimeric antibody, a chimeric antibody fragment that specifically binds to the target cell, a domain antibody, a domain antibody fragment that specifically binds to the target cell, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, or a nutrient-transport molecule. 
     
     
       18. The conjugate of  claim 17 , wherein the antibody is a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment; a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment thereof; a chimeric antibody fragment, a domain antibody, or a domain antibody fragment; a humanized antibody, a humanized single chain antibody, or a humanized antibody fragment. 
     
     
       19. A pharmaceutical composition comprising the conjugate of  claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
       20. A method of treating a cancer in a mammal, comprising administering to said mammal a therapeutically effective amount of the conjugate of  claim 9 , or a pharmaceutically acceptable salt thereof.